Lipopolysaccharide (LPS) is a major constituent of the outer membranes of gram-negative bacteria. Structural studies have shown that it consist of the following three distinct domains: 1) the O-antigen region, which is a strain-specific polysaccharide moiety and determines the antigenic speificity of the organism; 2) the core region, which is relatively conserved with respect to its sugar composition and may play a role in maintaining the integrity of the outer membrane; and 3) the lipid A region, which is also conserved and functions as a hydrophobic anchor holding lipopolysaccharide in place. The lipid A portion of lipopolysaccharide constitutes most of the outer monolayer of the outer membrane in gram-negatives.
Lipopolysaccharide is known to trigger many pathophysiological events in mammals, either when it is injected or when it accumulates due to gram-negative infection. In general, the hydrophobic lipid A moiety is responsible for these pathophysiolocical effects, which tend to be either immunostimulatory or toxic. In the former category there are events such as B-lymphocyte mitogenesis (1), macrophage activation (2), and the induction of tumor necrosis in certain experimental systems (3). In the latter (toxic) category there are responses such as peripheral vascular collapse ("endotoxic" shock) (4), pulmonary hypertension (5), pulmonary edema (6), disseminated intravascular coagulopathy (7) and pyrogenicity (8).
The complex events elicited by lipid A in mammals are not well understood at a molecular level, since the correct covalent structure of lipid A was unknown prior to 1983 (9, 10). The recent application of fast atom bombardment mass spectrometry and NMR spectroscopy to this problem, together with the recent discovery of a simple monosaccharide precursor (9), has led to the following proposed minimal structure of lipid A: ##STR1##
The above general structure of lipid A has been confirmed in Escherichia coli, Salmonella typhimurium and Salmonella minnesota. The discovery of the monosaccharide precursor, lipid X, has also led to the elucidation of the biosynthetic pathway for the formation of lipid A in E. coli and S typhimurium (11, 12). The availability of these various novel lipid A precursors and substructures has made it possible to dissect the chemical and structural requirements for the numerous biological effects of lipid A.